Transdermal compositions of 1-oxohydrocarbyl-substituted azacyclohexanes

ABSTRACT

This invention provides compositions for enhancing penetration of physiologically active agents through the skin or mucosal membranes and for retaining these agents in body tissues, said composition comprising effective amounts of a physiologically-active agent and a compound represented by the general formula ##STR1## wherein X may represent sulfur, oxygen or nitrogen; a and b may be 0 or 1, c may be 0, 1 or 2, except that when X is oxygen, a, b and c are 0, when X is nitrogen c is 0 and only one of a or b is 1, and when X is sulfur a and b are 0; A is a branched or a straight chain, divalent aliphatic radical having from 0 to 2 double bonds; R&#39; is selected from the group consisting of H, a lower alkyl group having from 1 to 4 carbon atoms, phenyl, lower alkyl or halogen substituted phenyl, acetamido, halogen, piperidinyl, lower alkyl or halogen substituted piperidinyl, carbalkoxy, carboxamide, and alkanoyl; and R is hydrogen or a lower alkyl group having from 1 to 4 carbon atoms, ##STR2## wherein R&#34; is H or halogen, and salts, e.g. acid or quaternary derivatives, thereof. These compositions are useful in topical or transdermal applications of the physiologically-active agent.

This application is a continuation of U.S. Ser. No. 06/897,043, entitledCOMPOSITIONS COMPRISING 1-OXOHYDROCARBYL-SUBSTITUTED AZACYCLOHEXANES,filed on Aug. 15, 1986, abandoned.

FIELD OF THE INVENTION

This invention relates to compositions comprising aphysiologically-active agent and a 1-oxohydrocarbyl-substitutedderivative of morpholine, thiomorpholine or piperazine in an amounteffective to enhance the penetration of the physiologically-active agentthrough the skin or other membrane of the body of an animal.

BACKGROUND OF THE ART

Many physiologically active agents are best applied topically to obtaindesirable results. Topical application, as contrasted to systemicapplication, can avoid metabolic degradation of the agents, largelyavoids side effects of the agents and permits high local concentrationsof the agents.

The greatest problem in applying physiologically active agents topicallyis that the skin is such an effective barrier to penetration. Theepidermis of the skin has an exterior layer of dead cells called thestratum corneum which is tightly compacted and oily and which providesan effective barrier against gaseous, solid or liquid chemical agents,whether used alone or in water or oil solutions. If a physiologicallyactive agent penetrates the stratum corneum, it can readily pass throughthe basal layer of the epidermis and into the dermis.

Although the effectiveness of the stratum corneum as a barrier providesgreat protection, it also frustrates efforts to apply beneficial agentsdirectly to local areas of the body. The inability of physiologicallyactive agents to penetrate the stratum corneum prevents their effectiveuse to treat such conditions as inflammation, acne, psoriasis, herpessimplex, eczema, infections due to fungus, virus or othermicroorganisms, or other disorders or conditions of the skin or mucousmembranes, or of conditions beneath the exterior surface of the skin ormucous membranes. The stratum corneum also prevents the skin fromabsorbing and retaining cosmetic-type materials such as sunscreens,perfumes, mosquito repellants and the like.

Physiologically active agents may be applied to locally affected partsof the body through the vehicle system described herein. Vehicles suchas USP cold cream, ethanol and various ointments, oils, solvents, andemulsions have been used heretofore to apply physiologically activeingredients locally. Most such vehicles are not effective to carrysignificant amounts of physiologically active agents through the skin.One such vehicle is dimethyl sulfoxide.

The 1-lower alkyl substituted azacyclopentan-2-ones having 1-4 carbonatoms in the alkyl group are known to moderately enhance percutaneousabsorption of chemicals, e.g. drugs. It was earlier recognized that itwould be desirable to obtain the same or higher level of percutaneousabsorption with substantially lower concentrations of thepenetration-enhancing compound. Therefore, various N-substitutedazacycloalkan-2-ones were invented having the desired properties. Thesenew penetration-enhancing agents are described in U.S. Pat. Nos.3,989,815; 3,989,816; 3,991,203; 4,122,170; 4,316,893; 4,405,616;4,415,563; 4,423,040; 4,424,210; and 4,444,762, which are herebyincorporated by reference.

It is an object of this invention to provide new penetration-enhancingagents having the desirable property of enhancing the percutaneousabsorption of physiologically-active agents at concentrations lower thanthe 1-lower alkyl substituted azacyclopentan-2-ones.

It is also an object of this invention to provide penetration-enhancingagents that are equivalent to the aforesaid new penetration-enhancingagents described in the above U.S. patents.

Other objects and advantages of the instant invention will be apparentfrom a careful reading of the specification below.

In this description, the term "animal" includes human beings as well asother forms of animal life, and especially domesticated animals andpets.

SUMMARY OF THE INVENTION

This invention relates to compositions for carrying physiologicallyactive agents through body membranes such as skin and for retainingthese agents in body tissues. More specifically, the invention relatesto compositions useful in topically administering a physiologicallyactive agent to a human or animal comprising the agent and an effective,non-toxic amount of a compound represented by the general formula##STR3## wherein X may represent sulfur, oxygen or nitrogen; a and b maybe 0 or 1, c may be 0, 1 or 2, except that when X is oxygen, a, b and care 0, when X is nitrogen c is 0 and only one of a or b is 1, and when Xis sulfur a and b are 0; A is a branched or a straight chain, divalentaliphatic radical having from 0 to 2 double bonds; R' is selected fromthe group consisting of H, a lower alkyl group having from 1 to 4 carbonatoms, phenyl, lower alkyl or halogen substituted phenyl, acetamido,halogen, piperidinyl, lower alkyl or halogen substituted piperidinyl,carbalkoxy, carboxamide, and alkanoyl; and R is hydrogen or a loweralkyl group having from 1 to 4 carbon atoms, ##STR4## wherein R" is H orhalogen, and salts, e.g. quaternary salts thereof.

Preferably R is hydrogen or a lower alkyl group, e.g. methyl, R' is H, Xis oxygen and A is a divalent radical represented by the general formula

    --CH.sub.2 --.sub.n

wherein n is 0 to 17.

In a more preferred embodiment of the present invention, n is 4-16, e.g.10.

It has been found that the physiologically active agents are carriedthrough body membranes by the above penetration-enhancing agents and areretained in body tissue.

The invention further relates to the penetration-enhancing agentsthemselves and the method of making such penetration-enhancing agents.

DETAILED DESCRIPTION OF THE INVENTION

1-oxohydrocarbyl-substituted derivatives of morpholine, thiomorpholineand piperazine, useful in the method of the present invention includecompounds represented by the general formulae: ##STR5## wherein R, R'and A are as defined above.

The compounds are also useful in the present invention as acid andquaternary derivatives. In particular, compounds represented by formulaII are conveniently converted into salts, e.g. acid and quaternaryderivatives represented by the general formula: ##STR6## In thecompounds represented by formula VII, R is preferably hydrogen or alower alkyl group, e.g. a methyl radical group.

These 1-oxohydrocarbyl-substituted derivatives, useful aspenetration-enhancing additives in the compositions of the instantinvention, may be made by the methods described below. Typical examplesof compounds represented by the above general formula include:

4-(1-oxododecyl)morpholine

2,6-dimethyl-4-(1-oxohexadecyl)morpholine

2,6-dimethyl-4-(1-oxooctadecyl)morpholine

2,6-dimethyl-4-(1-oxododecyl)morpholine

2,6-dimethyl-4-(1-oxotridecyl)morpholine

2,6-dimethyl-4-(1-oxotetradecyl)morpholine

2,6-dimethyl-4-(1-oxoundecyl)morpholine

4-(1-oxooctadecyl)morpholine

4-(1-oxononyl)morpholine

4-(1-oxodecyl)morpholine

4-(1-oxododecyl)morpholine

4-(1-oxohexadecyl)morpholine

4-(1-oxotetradecyl)morpholine

4-(1-oxooctyl)morpholine

4-(1-oxohexyl)morpholine

4-(1-oxoheptyl)morpholine

4-(1-oxopentyl)morpholine

4-(1-oxoundec-1-enyl)morpholine

4-(1-oxodeca-1,3-dienyl)morpholine

4-(1-oxononadecyl)morpholine

4-(1-oxundecyl)morpholine

4-(1-oxoheptadecyl)morpholine

4-(1-oxopentadecyl)morpholine

4-(1-oxo-16-methylheptadecyl)morpholine

2,6-dimethyl-4-(1-oxodecyl)morpholine

4-(1-oxotridecyl)morpholine

4,4-(1,6-dioxo-1,6-hexanediyl)bismorpholine

1-(1-oxohexadecyl)piperazine

1-(1-oxoheptadecyl)piperazine

1-(1-oxopentyl)piperazine

1,1'-(1,9-dioxo-1,9-nonanediyl)bispiperazine

1,1'-(1,10-dioxo-1,10-decanediyl)bis-piperazine

4,4'-(1,6-dioxo-1,6-hexanediyl)bis-thiomorpholine

1,1'-(1,10-dioxo-1,10-decanediyl)bis[4-methylpiperazine]

1,1'-(1,6-dioxo-1,6-hexanediyl)bis[4-methylpiperazine]

1,1'-(1,7-dioxo-1,7-heptanediyl)bis[4-methylpiperazine]

1,4-bis(1-oxodecyl)-piperazine

1-methyl-4-(1-oxodecyl)-piperazine

1,4-bis(1-oxododecyl)-piperazine

1-methyl-4-(1-oxohexyl)-piperazine

1,4-bis(1-oxohexyl)-piperazine

1,4-bis(1-oxoheptyl)-piperazine

1,4-bis(1-oxooctyl)-piperazine

1-(1-oxododecyl)-4-methyl-piperazine

1,4-bis(16-methyl-1-oxoheptadecyl)-piperazine

1,4-bis(1-oxohexadecyl)-piperazine

1,4-bis(1-oxooctadecyl)-piperazine

1-methyl-4-(1-oxohexadecyl)-piperazine

1-methyl-4-(1-oxooctadecyl)-piperazine

1-methyl-4-(1-oxoheptyl)-piperazine

1-methyl-4-(1-oxooctyl)-piperazine

1-methyl-4-(1-oxononyl)-piperazine

1-methyl-4-(1-oxotetradecyl)-piperazine

1-methyl-4-(1-oxoundecyl)-piperazine

1,1-dimethyl-4-(1-oxohexadecyl)piperazinium iodide

4-(1-oxododecyl)piperazinium chloride

Many of the compounds represented by the above general formula are wellknown. In addition, the Examples, below, illustrate methods forpreparing many of the compounds represented by the above generalformula. The amount of the 1-oxohydrocarbyl-substituted derivative whichmay be used in the present invention is an effective, non-toxic amountfor enhancing percutaneous absorption. Generally, this amount rangesbetween about 0.01 to about 5 and preferably about 0.1 to 2 percent byweight of the composition.

The subject compositions may find use with many physiologically activeagents which are soluble in the vehicles disclosed.

Fungistatic and fungicidal agents such as, for example, thiabendazole,chloroxine, amphotericin B, candicidin, fungimycin, nystatin,chlordantoin, clotrimazole, miconazole nitrate, pyrrolnitrin, salicylicacid, fezatione, tolnaftate, triacetin and zinc and sodium pyrithionemay be dissolved in the penetration-enhancing agents described hereinand topically applied to affected areas of the skin. For example,fungistatic or fungicidal agents so applied are carried through thestratum corneum, and thereby successfully treat fungus-caused skinproblems. These agents, thus applied, not only penetrate more quicklythan when applied in the vehicles of the prior art, but additionallyenter the animal tissue in high concentrations and are retained forsubstantially longer time periods whereby a far more successfultreatment is effected.

For example, the subject compositions may also be employed in thetreatment of fungus infections on the skin caused by candida anddermatophytes which cause athletes foot or ringworm, by dissolvingthiabendazole-or similar antifungal agents in one of the above-describedpenetration-enhancing agents and applying it to the affected area.

The subject compositions are also useful in treating skin problems, forexample, herpes simplex, which may be treated by a solution ofiododeoxyuridine dissolved in one of the penetration-enhancing agents orsuch problems as warts which may be treated with agents such aspodophylline dissolved in one of the penetration-enhancing agents. Skinproblems such as psoriasis may be treated by topical application of asolution of a conventional topical steroid in one of thepenetration-enhancing agents or by treatment with theophylline orantagonists of β-adrenergic blockers such as isoproterenol in one of thepenetration-enhancing agents. Scalp conditions such as alopecia areatamay be treated more effectively by applying steroids such astriamcinolone acetonide dissolved in one of the penetration-enhancingagents of this invention directly to the scalp.

The subject compositions are also useful for treating mild eczema, forexample, by applying a solution of fluocinolone acetonide or itsderivatives: hydrocortisone, triamcinolone acetonide, indomethacin, orphenylbutazone dissolved in one of the penetration-enhancing agents tothe affected area.

Examples of other physiologically active steroids which may be used withthe vehicles include corticosteroids such as, for example, cortisone,cortodoxone, flucetonide, fluorocortisone, difluorsone diacetate,flurandrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and its esters, chloroprednisone, clocortelone,descinolone, desonide, dexamethasone, dichlorisone, defluprednate,flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone,fluoromethalone, fluperolone, fluprednisolone, meprednisone,methylmeprednisolone, paramethasone, prednisolone and prednisone.

The subject compositions are also useful in antibacterial chemotherapy,e.g. in the treatment of skin conditions involving pathogenic bacteria.Typical antibacterial agents which may be used in this invention includesulfonamides, penicillins, cephalosporins, penicillinase, erythromycins,lincomycins, vancomycins, tetracyclines, chloramphenicols,streptomycins, etc. Typical examples of the foregoing includeerythromycin, erythromycin ethyl carbonate, erythromycin estolate,erythromycin glucepate, erythromycin ethylsuccinate, erythromycinlactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline,demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline,etc.

The subject compositions are also useful in protecting ultra-sensitiveskin or even normally sensitive skin from damage or discomfort due tosunburn. Thus, dermatitis actinica may be avoided by application of asunscreen, such as para-aminobenzoic acid or its wellknown derivativesdissolved in one of the above-described penetration-enhancing agents, toskin surfaces that are to be exposed to the sun; and the protectivepara-aminobenzoic acid or its derivatives will be carried into thestratum corneum more successfully and will therefore be retained evenwhen exposed to water or washing for a substantially longer period oftime than when applied to the skin in conventional vehicles. Thisinvention is particularly useful for ordinary suntan lotions used inactivities involving swimming because the ultraviolet screeningingredients in the carriers of the prior art are washed off the skinwhen it is immersed in water.

The subject compositions may also find use in treating scar tissue byapplying agents which soften collagen, such as aminopropionitrile orpenicillamine dissolved in one of the penetration-enhancing agents ofthis invention topically to the scar tissue.

Agents normally applied as eye drops, ear drops, or nose drops are moreeffective when dissolved in the penetration-enhancing agents of thisinvention.

Agents used in diagnosis may be used more effectively when applieddissolved in one of the penetration-enhancing agents of this invention.Patch tests to diagnose allergies may be effected promptly withoutscratching the skin or covering the area subjected to an allergen whenthe allergens are applied in one of the penetration-enhancing agents ofthis invention.

The subject compositions are also useful for topical application ofcosmetic or esthetic agents. For example, compounds such asmelanin-stimulating hormone (MSH) or dihydroxyacetone and the like aremore effectively applied to skin to stimulate a suntan when they aredissolved in one of the penetration-enhancing agents of this invention.The agent is carried into the skin more quickly and in greater quantitywhen applied in accordance with this invention. Hair dyes also penetratemore completely and effectively when dissolved in one of thepenetration-enhancing agents of this invention.

The effectiveness of such topically applied materials as insectrepellants or fragrances, such as perfumes and colognes, can beprolonged when such agents are applied dissolved in one of thepenetration-enhancing agents of this invention.

It is to be emphasized that the foregoing are simply examples ofphysiologically active agents including therapeutic and cosmetic agentshaving known effects for known conditions, which may be used moreeffectively for their known properties in accordance with thisinvention.

In addition, the penetration-enhancing agents of the present inventionmay also be used to produce therapeutic effects which were notpreviously known. That is, by use of the penetration-enhancing agentsdescribed herein, therapeutic effects heretofore not known can beachieved.

As an example of the foregoing, griseofulvin is known as the treatmentof choice for fungus infections of the skin and nails. Heretofore, themanner of delivery of griseofulvin has been oral. However, it has longbeen known that oral treatment is not preferred because of side effectsresulting from exposure of the entire body to griseofulvin and the factthat only the outer layers of affected skin need to be treated.Therefore, because fungal infections are generally infections of theskin and nails, it would be advantageous to utilize griseofulvintopically. However, despite a long-felt need for a topical griseofulvin,griseofulvin has been used orally to treat topical fungus conditionsbecause there was not heretofore known any formulation which could bedelivered topically which would cause sufficient retention ofgriseofulvin in the skin to be useful therapeutically.

However, it has now been discovered that griseofulvin, in a range oftherapeutic concentrations between about 0.1% and about 10% may be usedeffectively topically if combined with one of the penetration-enhancingagents described herein.

As a further example, acne is the name commonly applied to anyinflammatory disease of the sebaceous glands; also acne vulgaris. Themicroorganism typically responsible for the acne infection isCorynebacterium acnes. Various therapeutic methods for treating acnehave been attempted including topical antibacterials, e.g.hexachlorophene, and systemic antibiotics such as tetracycline. Whilethe systemic antibiotic treatments are known to be partially effective,the topical treatments are generally not effective.

It has long been known that systemic treatment of acne is not preferredbecause of side effects resulting from exposure of the entire body toantibiotics and the fact that only the affected skin need be treated.However, despite a long-felt need for a topical treatment for acne,antibiotics generally have been used only systemically to treat acnebecause there was not heretofore known an antibacterial formulationwhich could be used topically which would be effective therapeuticallyin the treatment of acne. However, it has now been discovered thatantibiotics, especially those of the lincomycin and erythromycinfamilies of antibiotics, may be used in the treatment of acne topicallyif combined with one of the penetration-enhancing agents describedherein.

The antibiotics composition so applied is carried into and through theepidermis and deeper layers of the skin as well as into follicles andcomedones (sebum-plugged follicles which contain C. acnes) intherapeutically effective amounts and thereby successfully may be usedto temporarily eliminate the signs and symptoms of acne.

The term "physiologically active agent" is used herein to refer to abroad class of useful chemical and therapeutic agents includingphysiologically active steroids, antibiotics, antifungal agents,antibacterial agents, antineoplastic agents, allergens, antihistaminicagents, anti-inflammatory agents, ultraviolet screening agents,diagnostic agents, perfumes, insect repellants, hair dyes, etc.

Dosage forms for topical application may include solution nasal sprays,lotions, ointments, creams, gels, suppositories, sprays, aerosols andthe like. Typical inert carriers which make up the foregoing dosageforms include water, acetone, isopropyl alcohol, freons, ethyl alcohol,polyvinylpyrrolidone, propylene glycol, fragrances, gel-producingmaterials, mineral oil, stearyl alcohol, stearic acid, spermaceti,sorbitan monooleate, "Polysorbates", "Tweens", sorbital, methylcellulose, etc.

The amount of the composition, and thus of the physiologically activeagent therein, to be administered will obviously be an effective amountfor the desired result expected therefrom. This, of course, will beascertained by the ordinary skill of the practitioner. Due to enhancedactivity which is achieved, the dosage of physiologically active agentmay often be decreased from that generally applicable. In accordancewith the usual prudent formulating practices, a dosage near the lowerend of the useful range of the particular physiologically active agentmay be employed initially and the dosage increased as indicated from theobserved response, as in the routine procedure of the physician.

The invention is further illustrated by the following examples which areillustrative of various aspects of the invention, and are not intendedas limiting the scope of the invention as defined by the appendedclaims.

EXAMPLE 1 ##STR7## Preparation of N-(1-Oxododecyl)morpholine

A) A suspension of 2.30g (57.0 mmol) of sodium hydride (60% oildispersion) in dry tetrahydrofuran (THF) and 5.0 g (57.0 mmol) ofmorpholine was refluxed under nitrogen for 30 minutes. After cooling,12.56 g (57.0 mmol) of dodecanoyl chloride in THF was added dropwise,and the mixture was refluxed 30 minutes. Water was added, and themixture was extracted with ethyl acetate (EtOAc). The combined organicphase was dried with MgSO₄, concentrated in vacuo, and purified by flashchromatography (8:1 hexane/EtOAc) to give N-(oxododecyl)morpholine, asconfirmed by NMR & IR spectroscopy.

Anal. Calcd. for C₁₆ H₃₁ NO₂ : C, 71.32; H, 11.60; N, 5.20. Found: C,71.09; H, 11.5 ; N, 5.15.

B) Example 1(A) was repeated using morpholine/dodecanoyl chloride and anorganic base, e.g. triethylamine, in dry toluene at room temperaturefollowed by filtration and chromatography to yield the above product.

C) Example 1(A) was repeated using morpholine, potassium carbonate anddodecanoyl chloride in a biphasic mixture of chloroform and waterfollowed by the usual workup to obtain the above product.

EXAMPLE 2 ##STR8##

Example 1 was repeated using ethyl 1-piperazinecarboxylate instead ofmorpholine followed by hydrolysis to obtain N-(1-oxododecyl)piperazine.

EXAMPLE 3 ##STR9##

Example 1 was repeated using piperazine and two equivalents ofdodecanoyl chloride to obtain 1,4-bis(1-oxododecyl)-piperazine.

EXAMPLE 4 ##STR10##

The product of Example 2 was dissolved in methanol and treated with HClgas to obtain 1,1-dihydrogen-4-(1-oxododecyl)piperazinium chloride.

EXAMPLE 5 ##STR11##

Example 1 was repeated using thiomorpholine in place of morpholine withdodecanoyl chloride to obtain N-(1-oxododecyl)thiomorpholine.

EXAMPLE 6

The compound of Example 1 was tested as a penetration enhancing agentaccording to the below procedure:

Skin from female hairless mice, 4-6 weeks old, was removed from theanimal and placed over penetration wells with normal saline bathing thecorium. A plastic cylinder 1.4 cm in diameter was glued onto each pieceon the epidermal side. 0.1% triamcinolone acetonide ³ H was applied(0.01 cc) to the epidermal surface within the 1.4 cm diameter cylinder.The skin was incubated at room temperature and ambient humidity.

At 6 hours and 24 hours, 2 cc were removed from the 10 cc reservoir ofnormal saline bathing the corium. The 2 cc of normal saline removed werereplaced after the 6 hour sample with 2 cc of normal saline.

The 2 cc aliquots were put into scintillation fluid and theradioactivity determined in a scintillation counter. The amountpenetrating was calculated as per cent of dose applied.

In every experiment the ³ H triamcinolone acetonide was dissolved inethanol and the penetration-enhancing agent to be tested was added tothe desired concentration.

The controls were ethanol, alone, and 1-n-dodecylazacycloheptan-2-one, acompound described in the U.S. patents, noted above, as having superiorpenetration enhancing properties. Five separate tests for each compoundand the controls were made and the results averaged.

The results, as reported in the Table below, show that the compounds ofExample 1 has penetration-enhancing properties at least equivalent to1-n-dodecylazacycloheptan-2-one.

                  TABLE                                                           ______________________________________                                        Penetration-Enhancing                                                                           Percent Penetration                                         Agent             6 Hr.   24 Hr.                                              ______________________________________                                        N-(1-oxododecyl)morpholine                                                                      14.9    53.2                                                1-n-Dodecylazacycloheptan-2-one                                                                 12.6    54.1                                                Ethanol (only)     0.4     3.8                                                ______________________________________                                    

EXAMPLE 7

The following formulation is prepared:

    ______________________________________                                                         Solution (%)                                                 ______________________________________                                        Griseofulvin       1                                                          N-(1-oxododecyl)morpholine                                                                       1                                                          Isopropyl myristate                                                                              5                                                          Fragrance          0.1                                                        Ethanol            92.9                                                       ______________________________________                                    

This formulation is effective in the treatment of fungus infections.

EXAMPLE 8

An aerosol form of the formulation of Example 7 is prepared by preparingthe following mixture:

    ______________________________________                                               Formulation                                                                            25%                                                                  Freon.sup.1                                                                            75%                                                           ______________________________________                                         .sup.1 Freon is 75/25 Freon 114/12.                                      

EXAMPLE 9

The following cream formulation is prepared:

    ______________________________________                                                           %                                                          ______________________________________                                        Clindamycin base     1.0                                                      Stearyl alcohol, U.S.P.                                                                            12.0                                                     Ethoxylated cholesterol                                                                            0.4                                                      Synthetic spermaceti 7.5                                                      Sorbitan monooleate  1.0                                                      Polysorbate 80, U.S.P.                                                                             3.0                                                      N-(1-Oxododecyl)morpholine                                                                         0.5                                                      Sorbitol solution, U.S.P.                                                                          5.5                                                      Sodium citrate       0.5                                                      Chemoderm #844 Fragrance                                                                           0.2                                                      Purified Water       68.4                                                     ______________________________________                                    

This formulation is effective in the treatment of acne.

EXAMPLE 10

The following solution formulations are prepared:

    ______________________________________                                                           A (%) B (%)                                                ______________________________________                                        Clindamycin base     --      1.0                                              Clindamycin phosphate acid                                                                         1.3     --                                               Sodium hydroxide     0.077   --                                               1.0M Hydrochloric acid                                                                             --      2.27                                             Disodium edetate.2H.sub.2 O                                                                        0.003   0.003                                            Fragrances           0.5     0.5                                              N-(1-Oxododecyl)morpholine                                                                         1.0     1.0                                              Purified water       20.0    17.73                                            Isopropanol          77.12   77.497                                           ______________________________________                                    

These solutions are effective for the treatment of acne in humans.

EXAMPLE 11

The following solution formulation is prepared:

    ______________________________________                                                          %                                                           ______________________________________                                        Neomycin sulfate    0.5                                                       Lidocaine           0.5                                                       Hydrocortisone      0.25                                                      N-(1-Oxododecyl)morpholine                                                                        0.5                                                       Propylene glycol    98.25                                                     ______________________________________                                    

This solution is effective for the treatment of otitis in domesticanimals.

EXAMPLE 12

The following sunscreen emulsion is prepared:

    ______________________________________                                                          %                                                           ______________________________________                                        p-Aminobenzoic acid 2.0                                                       Benzyl alcohol      0.5                                                       N-(1-Oxododecyl)morpholine                                                                        1.0                                                       Polyethylene glycol 500-MS                                                                        10.0                                                      Isopropyl lanolate  3.0                                                       Lantrol             1.0                                                       Acetylated lanolin  0.5                                                       Isopropyl myristate 5.0                                                       Light mineral oil   8.0                                                       Cetyl alcohol       1.0                                                       Veegum              1.0                                                       Propylene glycol    3.0                                                       Purified water      64.0                                                      ______________________________________                                    

EXAMPLE 13

The following antineoplastic solution is prepared:

    ______________________________________                                                          %                                                           ______________________________________                                        5-Fluorouracil      5.0                                                       N-(1-Oxododecyl)morpholine                                                                        0.1                                                       Polyethylene glycol 5.0                                                       Purified water      89.9                                                      ______________________________________                                    

EXAMPLE 14

The following insect repellant atomizing spray is prepared:

    ______________________________________                                                          %                                                           ______________________________________                                        Diethyltoluamide    0.1                                                       N-(1-Oxododecyl)morpholine                                                                        0.1                                                       Ethanol             99.8                                                      ______________________________________                                    

EXAMPLE 15

The following lotion formulation may be prepared containing about 0.001to 1 percent, with preferably 0.1 percent fluocinolone acetonide:

    ______________________________________                                                          %                                                           ______________________________________                                        Fluocinolone acetonide                                                                             0.001-1                                                  Cetyl alcohol        15.0                                                     Propylene glycol     10.0                                                     Sodium lauryl sulfate                                                                              15.0                                                     N-(1-Oxododecyl) morpholine                                                                         1.0                                                     Water (to make 100%)                                                          ______________________________________                                    

The steroid is dissolved in the vehicle and added to a stirred, coolingmelt of the other ingredients. The preparation is particularly usefulfor the treatment of inflamed dermatoses by topical application to theaffected skin area. The amount and frequency of application is inaccordance with standard practice for topical application of thissteroid. Penetration of the steroid into the inflamed tissue is enhancedand a therapeutic level is achieved more rapidly and sustained forlonger duration than when the steroid is applied in conventionalformulations.

EXAMPLE 16

Examples 7-15 are repeated except that N-(1-oxododecyl)morpholine isreplaced with the compounds of Examples 2, 3, 4 and 5. Comparableresults are obtained.

While particular embodiments of the invention have been described itwill be understood of course that the invention is not limited theretosince many obvious modifications can be made and it is intended toinclude within this invention any such modifications as will fall withinthe scope of the appended claims.

Having now described the invention, we claim:
 1. A pharmaceuticalcomposition comprising an effective amount of a physiologically activeagent selected from the group consisting of lincomycin, clindamycin,erythormycin, and pharmaceutically useful salts thereof, or from thegroup consisting of iododeoxyuridine and 5-fluorouracil, and anon-toxic, effective penetrating amount of a compound represented by thegeneral formula ##STR12## wherein X may represent sulfur, oxygen ornitrogen; a and b may be 0 or 1, c may be 0, 1 or 2, except that when Xis oxygen, a, b and c and 0, when X is nitrogen c is 0 and only one of aor b is 1, and when X is sulfur a and b are 0; A is a branched or astraight chain, divalent aliphatic radical having up to 17 carbon atomsand from 0 to 2 double bonds; R' is selected from the group consistingof H, a lower alkyl group having from 1 to 4 carbon atoms, phenyl, loweralkyl having from 1 to 4 carbon atoms or halogen substituted phenyl,acetamido, halogen, piperidinyl, lower alkyl having from 1 to 4 carbonatoms or halogen substituted piperidinyl, or carboxamide; and R ishydrogen or a lower alkyl group having from 1 to 4 carbon atoms,##STR13## wherein R" is H or halogen, and salts thereof, together with apharmaceutically acceptable carrier.
 2. The composition of claim 1wherein the agent is selected from the group consisting of lincomycin,clindamycin, erythromycin and pharmaceutically useful salts thereof. 3.The composition of claim 1 wherein the physiologically active agent isiododeoxyuridine.
 4. The composition of claim 1 wherein thephysiologically active agent is 5-fluorouracil.
 5. A pharmaceuticalcomposition useful for enhancing penetration of a physiologically activeagent selected from the group consisting of lincomycin, clindamycin,erythromycin, and pharmaceutically useful salts thereof, or from thegroup consisting of iododeoxyuridine and 5-fluorouracil, topicallyadministered to a human or animal comprising an effective amount of aphysiologically active agent and non-toxic, effective penetrating amountof a penetration enhancer represented by the general formula ##STR14##wherein n is 4-16 and R is --CH₃ and salts thereof, together with apharmaceutically acceptable carrier.
 6. The composition of claim 5wherein n is 10 and R is methyl.
 7. The composition of claim 5 whereinthe antibiotic is selected from the group consisting of lincomycin,clindamycin, erythromycin and pharmaceutically useful salts thereof. 8.The composition of claim 5 wherein the physiologically active agent isiododeoxyuridine.
 9. The composition of claim 5 wherein thephysiologically active agent is 5-fluorouracil.
 10. A method forenhancing penetrability of the skin or mucous membrane so as toadminister an effective amount of a physiologically active agentselected from the group consisting of lincomycin, clindamycin,erythromycin, and pharmaceutically useful salts thereof, or from thegroup consisting of iododeoxyuridine and 5-fluorouracil, through theskin or mucosal membrane of a human or animal and retain saidphysiologically active agent in the body tissues, which method comprisescontacting said skin or mucosal membrane with a compound of the generalformula ##STR15## wherein X may represent sulfur, oxygen or nitrogen; aand b may be 0 or 1, c may be 0, 1 or 2, except that when X is oxygen,a, b and c are 0, when X is nitrogen c is 0 and only one of a or b is 1,and when X is sulfur a and b are 0; A is a branched or a straight chain,divalent aliphatic radical having up to 17 carbon atoms and from 0 to 2double bonds; R' is selected from the group consisting of H, a loweralkyl group having from 1 to 4 carbon atoms, phenyl, lower alkyl havingfrom 1 to 4 carbon atoms or halogen substituted phenyl, acetamido,halogen, piperidinyl, lower alkyl having from 1 to 4 carbon atoms orhalogen substituted piperidinyl, or carboxamide; and R is hydrogen or alower alkyl group having from 1 to 4 carbon atoms, ##STR16## wherein R"is H or halogen, and salts thereof.
 11. The method of claim 10 whereinthe agent is selected from the group consisting of lincomycin,clindamycin, erythromycin and pharmaceutically useful salts thereof. 12.The method of claim 10 wherein the physiologically active agent isiododeoxyuridine.
 13. The method of claim 10 wherein the physiologicallyactive agent is 5-fluorouracil.
 14. A method for topically administeringa physiologically active agent selected from the group consisting oflincomycin, clindamycin, erythromycin, and pharmaceutically useful saltsthereof, or from the group consisting of iododeoxyuridine and5-fluorouracil, to a human or animal in need of such treatment whichcomprises contacting said skin or mucosal membrane of the human oranimal with an effective amount of a physiologically active agent in thepresence of a non-toxic, effective penetrating amount of a compoundrepresented by the general formula ##STR17## wherein n is 4-16 and R is--CH₃ and salts thereof.
 15. The method of claim 14 wherein the agent isselected from the group consisting of lincomycin, clindamycin,erythromycin and pharmaceutically useful salts thereof.
 16. The methodof claim 14 wherein the physiologically active agent isiododeoxyuridine.
 17. The method of claim 14 wherein the physiologicallyactive agent is 5-fluorouracil.